Preparation of an Atorvastatin Intermediate

ABSTRACT

The diketone of atorvastatin is prepared by first washing a reaction vessel with a non-ketonic solvent, especially tetrahydrofuran, to remove water. 4-fluorobenzaldehyde is then reacted with benzylidine isobutyryl acetanilide in the reaction vessel to form 4-fluoro-alpha-(2-methyl-1-oxopropyl)-gamma-oxo-N,beta-diphenylbenzene-butanainide

The invention relates to a process for preparing the diketone ofatorvastatin which is a key intermediate in the preparation ofatorvastatin lactone. Atorvastatin lactone is a trans-6-[2-(substitutedpyrrole-1-yl)alkyl]pyran-2-one which is known by the chemical name(2R-trans)-5-(4-fluorophenyl)-2-(1-methyethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide.

Atorvastatin lactone is the penultimate intermediate in the preparationof another trans-6-[2-(substituted pyrrole-1-yl)alkyl]pyran-2-one,atorvastatin calcium known by the chemical name[R—R*,R*)]-2-4fluorophenyl-β,δ-dihydroxy-5-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid hemi calcium salt.

Atorvastatin as well as some of its metabolites is pharmacologicallyactive in humans and is useful as a hypolipidemic andhypocholesterolemic agent. In particular, atorvastatin is useful as aselective and competitive inhibitor of the enzyme3-hydroxy-3-methylglutaryl-coenzyme A (HMO-CoA) reductase, therate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme Ato mevalonate, a precursor of sterols such as cholesterol. Theconversion of HMG-CoA to mevalonate is an early and rate-limiting stepin cholesterol biosynthesis.

U.S. Pat. No. 4,681,893, which is herein incorporated by reference,discloses certain trans- 6-[2-(3- or4-carboxamido-substituted-pyrrol-1-yl)alkyl)]4-hydroxy-pyran-2-onesincluding trans(±)-5-(4fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[(2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]1H-pyrrole-3-carboxamide.

U.S. Pat. No. 5,273,995, which is herein incorporated by reference,discloses the enantiomer having the R form of the ring-opened acid oftrans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4diphenyl-1-[(2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide,i.e., [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid.

The above described atorvastatin compounds have been prepared by asuperior convergent route disclosed in the following U.S. Pat. Nos.5,003,080; 5,097,045; 5,03,024; 5,124,482 and 5,149,837 which are hereinincorporated by reference and Baumann K. L., Butler D. E., Deering C.F., et al, Tetrahedron Letters 1992;33:2283-2284.

One of the critical intermediates outlined in U.S. Pat. No. 5,097,045has also been produced using novel chemistry, as described in U.S. Pat.No. 5,155,251, which is herein incorporated by reference and Brower P.L., Butler D. E., Deering C. F., et al, Tetrahedron Letters1992;33:2279-2282.

U.S. Pat. Nos. 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,397,792;5,342,952; 5,298,627; 5,446,054; 5,470,981; 5,489,690; 5,489,691;5,5109,488; WO97/03960; WO98/09543 and WO99/32434 which are hereinincorporated by reference, disclose various processes and keyintermediates for preparing atorvastatin.

The process for preparing atorvastatin intermediates is particularlysensitive and vulnerable to the formation of process impurities whichmay cause product rejection and decreased yields.

The object of the present invention is therefore to provide an improvedprocess for preparing atorvastatin intermediates in which the formationof reaction impurities is minimised.

STATEMENTS OF INVENTION

According to the present invention there is provided a process for theproduction of the diketone of atorvastatin comprising the steps of:

-   -   washing a reaction vessel with a non-ketonic solvent to remove        water; and    -   reacting 4-fluorobenzaldehyde with benzylidine isobutyryl        acetanilide in the reaction vessel to form        4-fluoro-alpha-(2-methyl-1-oxopropyl)-gamma-oxo-N,beta-diphenylbenzenebutanamide        according to the following reaction scheme:

Preferably the non-ketonic solvent is tetrahydrofuran.

In one embodiment the process includes the step of collecting thewash-off material and discharging it from the vessel prior to theintroduction of the reactants.

In a further embodiment the non-ketonic solvent is introduced into thereaction vessel through a spray ball to substantially cover all of theinner surfaces of the vessel. The reaction vessel includes an agitatorwhich is also dried by the non-ketonic solvent.

DETAILED DESCRIPTION

The invention will be more clearly understood from the followingdescription thereof given by way of example only.

The diketone of atorvastatin or4-fluoro-alpha-(2-methyl-1-oxopropyl)-gamma-oxo-N,beta-diphenylbenzenebutanamide,is prepared in a single step by the reaction of 4-fluorobenzaldehydewith 2-benzylidine isobutyryl acetanilide in a Stetter reaction as shownin scheme 1.

Impurities which have been detected in the diketone of atorvastatinarise from unreacted starting material, impurities derived from startingmaterial contaminants and reaction by-products. The process isparticularly sensitive to the presence of trace amounts of water whichcan cause the formation of several process impurities such as desfluorodiketone.

We have found that by washing and drying the reaction equipment with anon-ketonic solvent a significant reduction in impurity formation can beachieved. Previously the reaction equipment was washed with acetonewhich is the solvent of choice for such applications in view of itsready availability, relatively low cost, low boiling point and watermiscibility.

However, we have found that even trace amounts of acetone react with thealdehyde starting material to form water. The presence of water in turnencourages the formation of undesirable desfluro diketone impurities.

The desfluro diketone impurity is of very similar structure to thedesired diketone as will be apparent from scheme 2.

While other impurities may be readily removed from the reaction processusing recrystallisation, the desfluro diketone impurity is especiallyproblematic. If the desfluro impurity is above 0.45% the product hasfailed and cannot be recovered. If the desfluro impurity is less thanabout 0.45% it may be possible to recover the product after one or morerecrystallisation steps.

Tetrahydrofuran (THF) was found to be the ideal non-ketonic solvent asat ambient temperature it dissolves diketone with the advantage of noadverse effect on the reaction as it is already used as a reactionsolvent. It is also a dry solvent with a low water specification of0.03%.

The present invention therefore provides an improved process for thepreparation of the diketone of atorvastatin, a key intermediate in thepreparation of atorvastatin lactone.

EXAMPLE 1 Preparation of4-fluoro-alpha-[2-methyl-1-oxopropyl]-gamma-oxo-N,beta-diphenylbenzenebutanamide

A reaction vessel is inerted using at least 4 cycles of vacuum,releasing the vacuum each time with nitrogen. 250 litres oftetrahydrofuran is charged to the reaction vessel via spray nozzles.Spray ball nozzles ensure that all areas of the reaction vessel arepenetrated in particular the top inner surface of the vessel and theagitator device also present inside the reaction vessel. Thetetrahydrofuran washings are drained off and collected for wasterecycling.

When the reaction vessel is dry 480 kgs 2-benzylidineisobutyrylacetamide (BIBEA), 60 kgs ethyl hydroxyethylmethyl thiazoliumbromide (MTB or ethyl hydroxyethyl MTB), 200 litres, 216 kgs of4-fluorobenzaldehyde and 120 kgs of triethylamine are charged to thereaction vessel and heated with agitation to between 60 and 70° C. Thereaction mixture is aged for 16 to 24 hrs maintaining the temperature at65+/−5° C. The contents are then cooled to 60+/−5° C. for 54 to 66minutes. 600 litres of isopropanol is charged to the reaction mixtureand the mixture is heated to about 100° ° C. to achieve a solution.

600 litres of deionised water is charged to the reaction vessel over 30minutes while maintaining the temperature at 60+/−5° C. The batch isaged for 54 to 66 minutes and the contents cooled to between 25+/−5° C.over a 2 to 4 hour period at a rate of 15/20° C. per hour. The batch isaged at this temperature for at least 1 hour and the contents cooledfurther to 0+/−5° C. and aged for at least 1 hour.

The batch is isolated on a filter and washed with isopropanol. Theproduct is dried under-vacuum at 50+/−5° C. to a water content of lessthan 0.5%. The contents are then cooled to approximately less than 30°C. before discharging.

The invention is not limited to be embodiments hereinbefore describedwhich may be varied in detail.

1. A process for the production of the diketone of atorvastatincomprising the steps of : washing a reaction vessel with a non-ketonicsolvent to remove water; and reacting 4-fluorobenzaldehyde withbenzylidine isobutyryl acetanilide in the reaction vessel to form4-fluoro-alpha-(2-methyl-1-oxopropyl)-gamma-oxo-N,beta-diphenylbenzenebutanamideaccording to the following reaction scheme:


2. A process as claimed in claim 1 wherein the non-ketonic solvent istetrahydrofuran.
 3. A process as claimed in claim 1 or 2 including thestep of collecting the wash-off material and discharging it from thevessel prior to the introduction of the reactants.
 4. A process asclaimed in any preceding claim wherein the non-ketonic solvent isintroduced into the reaction vessel through a spray ball tosubstantially cover all of the inner surfaces of the vessel.
 5. Aprocess as claimed in any preceding claim wherein the reaction vesselincludes an agitator which is also dried by the non-ketonic solvent.